NIH to Order New Reports on Past Gene Therapy Cases

The National Institutes of Health soon will order scientists who have conducted gene therapy research to open their old files and report all past instances of side effects during trials.

The dramatic federal action comes after recent revelations that gene therapy researchers violated NIH reporting rules and follows the death last fall of an Arizona man who was participating in a gene therapy trial. It covers more than 400 trials conducted with more than 4,000 patients during the last decade.

“This is a major effort and it won’t be an easy task,” said Lana Skirboll, director of NIH’s office of science policy, which plays a leading role in gene therapy research. She was one of several NIH sources to confirm the development.

The new policy will look at the history of gene therapy research--which has come under increasing national scrutiny in recent months--in an attempt to identify problematic trends that might have been overlooked, missed or ignored.

“We don’t think we can simply start from here and move on,” Skirboll said in an interview.

Researchers engaged in trials past and present will receive telephone calls, followed by letters, alerting them to the new enforcement policy, Skirboll said. So will their institutions and institutional review boards, the local panels that review research proposals.

The reporting crackdown is one of several steps that NIH officials are undertaking in cooperation with the Food and Drug Administration to tighten oversight on researchers who disobey requirements on reporting adverse effects, which can range from the very mild, such as low-grade fevers, to the most severe, such as liver failure.

“We want to make sure our message is clear: that the past degree of noncompliance was unacceptable and . . . we won’t tolerate it,” Skirboll said.

The NIH said that it also plans to visit some NIH-funded institutions, not to find fault but to ensure that researchers understand what is required and to identify any problems associated with their compliance.

And a memorandum already has been sent to institutions that conduct gene therapy research asking them to review their existing policies to ensure that they comply.

In a related development, Rep. Henry A. Waxman (D-Los Angeles) released new information Wednesday showing more apparent reporting lapses by gene therapy researchers and faulting the NIH for its failure to respond with adequate oversight.

Waxman, who obtained his information from records provided to him by the NIH, asked the agency to explain the way several cases were handled.

The earliest gene therapy experiments took place at the NIH in 1990, and the work still is viewed by many as a potentially cutting-edge treatment for a range of diseases caused by genetic flaws. The approach involves finding ways to introduce modified genes that will correct or replace defective genes.

Typically, patients are recommended for research trials by their physicians. In many cases, but not all, gene therapy--because of its novel nature--is conducted on patients who may have terminal illnesses and may have failed conventional therapies. That often makes it difficult when patients die to determine with any certainty whether the experimental therapy or the underlying disease was responsible.

The research has been controversial since the death of 18-year-old Jesse Gelsinger of Tucson. Gelsinger died in September after receiving experimental gene therapy for a liver disorder at the University of Pennsylvania’s Institute of Gene Therapy.

He had volunteered for the experimental treatment with the hope of curing his rare genetic disorder, ornithine transcarbamylase deficiency, which prevents the liver from breaking down ammonia, a normal byproduct of protein digestion.

He died after researchers infused a genetically modified virus into his liver in an attempt to introduce new genes that could correct those responsible for his ailment.

Since Gelsinger died, the FDA has determined that the institute violated several federal regulations in its conduct of the study and halted all gene therapy trials there.

Unlike most biomedical research areas, which are monitored solely by the FDA, the gene therapy field has been subject to unusual joint oversight from both the NIH and the FDA. And both agencies have been working together in recent months to cooperatively sharpen their monitoring.

One of the NIH’s chief mandates is to inform the public, while the FDA has regulatory authority over the trials and can halt them when it finds that there are problems.

Notification rules of the two agencies differ. Researchers are required to report all adverse events immediately to the NIH--even if they seem unrelated to their experiment. The information is reviewed by the NIH’s Recombinant DNA Advisory Committee, whose members often discuss it in public forums.

Researchers must also notify the FDA of adverse events immediately. But the urgency applies only to dangerous side effects deemed “unexpected” or “related” to the therapy. And unlike the NIH, the FDA is not allowed to make the information public.

Because of these differences, the NIH has asked an advisory subcommittee to reassess what should be reported to the NIH and when it should be reported. Members of the group are expected to discuss their proposals at a meeting next month.

At the same time, numerous researchers have acknowledged their failure to report side effects to the NIH as required. Some have complained privately that the government’s reporting rules are burdensome--and ineffective. And others are uncomfortable with the NIH’s making information public.

In his letter to the NIH, Waxman cited a 1996 patient death during a cystic fibrosis gene therapy trial at the University of Pennsylvania’s Institute of Gene Therapy--the same facility where Gelsinger died.

Researchers reportedly told the NIH that they would provide test results to ensure that the death was not related to gene therapy. “But no results were apparently provided by the investigator or sought by NIH,” Waxman wrote to Dr. Ruth Kirschstein, acting director of the NIH.

In a second trial, of terminal lung cancer patients at the M.D. Anderson Cancer Center in Houston, Waxman questioned why the NIH had taken no action to investigate the deaths of 38 of the program’s 48 patients to make sure that they were from the illness and not the treatment.